Use for pharmaceutical composition

ABSTRACT

The invention relates to the use of one or more cannabinoids in the treatment of neuropathic or chronic pain.

FIELD OF THE INVENTION

The invention relates to the use of one or more cannabinoids in thetreatment of neuropathic or chronic pain.

BACKGROUND TO THE INVENTION

The brachial plexus is formed from a group of combining spinal nervesthat eventually divide to form the entire motor and sensory supply tothe upper limb. Trauma to these nerves is associated with paralysis,loss of sensation and frequently chronic pain. Initial treatment is torepair the nerve damage through surgery. Although this surgery is oftensuccessful in restoring motor function, patients are often left withlong term pain. The few studies which have reviewed pain followingbrachial plexus injury have shown that this pain is particularlydifficult to treat.¹ Drugs are available to treat the pain but they havelimited efficacy and are often associated with side effects. Improvedtreatments are urgently needed for this patient group.

Cannabis plants (Cannabis sativa) contain over 60 differentcannabinoids². In the UK until 1971, British Doctors could prescribeoral tinctures of cannabis. ³ Subsequently, cannabis and cannabinoidswere placed in Schedule 1 of the Misuse of Drugs Act 1971 and for thepast four decades, cannabis has been associated with illicitrecreational use, largely by smoking dried plant material or resin fromthe flower heads to obtain a rapid absorption from the lung, giving aeuphoric state or ‘high’. The principal psychoactive component incannabis preparations is considered to be the cannabinoid Δ⁹tetrahydrocannabinol (THC).

Cannabinoids affect almost every body system and like any other drug mayhave side effects.⁴ These are not usually severe and compare favourablywith many other drugs with similar therapeutic targets for example;tricyclic antidepressants, phenothiazines, opioid and non-opioidanalgesics and anticonvulsants. It has been estimated, based onextrapolation from mouse to man, that the lethal dose to effective dose(LD/ED) ratio is about 40,000 to 1.⁸ There have been no recorded deathsdirectly attributable to cannabis alone whereas in the UK approximately600 people die each year following gastrointestinal haemorrhage, largelyassociated with NSAID use.⁷

Known pharmacological effects of cannabinoids⁴ include psychologicaleffects, effects on perception, cognition, psychomotor performance andmotor function, and analgesic, anti-emetic and sedative effects.Cannabinoids are known to cause a decrease in intra-ocular pressure andan increase in appetite. There are also cardiovascular effects;tachycardia and increased cerebral blood flow (with acute use),bradycardia and decreased cerebral blood flow (with chronic use),vasodilation and increased cardiac output. Effects on the respiratorysystem include bronchodilatation, airways obstuction (from smoking), andeffects on ventilation. Aggravation of psychosis may occur in patientswith schizophrenia.

Whether the recreational use of cannabis encourages escalation of dosageand progression to other dependency-producing drugs remains debatable.Many other therapeutic drugs have an abuse potential that might beconsidered to be more harmful and less reversible such as;benzodiazepines and opioids. However, experience with patients receivingopioids for pain relief shows that therapeutic use rarely leads tomisuse,^(8,9) and the same is likely to apply to cannabinoids.Withdrawal symptoms from cannabinoid use are said to be short-lived (afew days) and mild in normal experimental subjects.³ Experience with theclinical use of Nabilone indicates that this is probably a minor andoccasional problem. Psychological dependency definitely occurs in asmall minority of recreational users. Some workers take the view thatthere is also a modest physical withdrawal syndrome when heavy usersabruptly abstain,⁴ though this seems to be limited to a few nights ofsleep disturbance and somatic anxiety symptoms.

A body of anecdotal evidence has emerged that suggests that patientswith a range of conditions and, diseases can obtain significant symptomrelief from illicit or ‘street’ cannabis. The evidence base includesreports from patients with rheumatoid arthritis, neuropathic pain,cancer pain and multiple sclerosis (MS).⁶ Cannabis use has tended tohappen amongst patients with severe or intolerable symptoms thatconventional therapies had failed to relieve and who had tried cannabisas a last resort.

Subsequently, interest has grown and research has been conducted intothe therapeutic uses of cannabinoids.² This research has not been partof a coordinated programme and has involved small trials, often insingle indications and has focussed mainly on purified oral formulationsof the main psychoactive component, THC. One placebo-controlled study oforal THC in nine patients showed a statistically significant reductionin spasticity compared with placebo.¹² A second placebo controlled studyof oral THC in 13 patients reported significant subjective improvementsin spasticity.¹³ In many other cases however, the results have beeninconclusive, but benefits have been evident even in small trials. Thesecontradictory results are probably because routes of administrationinvolving the gastro-intestinal tract (oral, rectal) are slow andproduce variable effects, due to the poor and varied absorption from thegut. In these settings it has been difficult to titrate cannabinoidsaccurately to a therapeutic effect.

Currently the synthetic cannabinoid Nabilone® is the only cannabinoidpreparation with a licence for medicinal use in the UK. Nabilone®capsules are indicated for intractable nausea and vomiting associatedwith cytotoxic chemotherapy. There has been insufficient evidence tosecure regulatory approval in any other indications. Purification of asingle cannabinoid may be a contributory factor in limiting efficacy intherapeutic areas where strong anecdotal evidence has suggested atherapeutic benefit from smoked cannabis. A mixture of many cannabinoidsis delivered when cannabis is smoked,² but smoking clearly is aninappropriate delivery system for a medicinal product. The smoke isinconsistent in composition and contains potential carcinogens fromincomplete combustion, similar to tobacco smoke.⁴

The findings of the House of Lords Select Committee on Science andTechnology recommended that clinical trials of cannabis for thetreatment of MS and chronic pain be mounted as a matter of urgency andthat research should be promoted into alternative modes ofadministration which would retain the benefits of the rapid absorptionoffered by smoking without the associated adverse effects (Section 28,References, 1). The Institute of Medicine report on medicinal cannabisalso recommended that therapeutic trials be undertaken on non smokedforms of cannabis-based medicines.¹¹

The applicant has developed cannabis based medicinal extracts (CBME),from whole cannabis plants as disclosed in WO 02/064109. The extractsare derived from strains of plants developed to produce high andreproducible yields of specified cannabinoids. The extracts from theseplants contain a defined amount of the major cannabinoid, plus traceamounts of minor cannabinoids. The major cannabinoids constitute notless than 90% of the total cannabinoid content of the extracts. It isthought that the minor cannabinoids may add to the overall therapeuticprofile of the CBMEs and may play a role in stabilising the majorcomponents. Currently, two CBME preparations have reached phase 3clinical studies, “THC” in which Δ⁹ tetrahydrocannabinol is the majorcannabinoid, and “THC:CBD 1:1”, containing substantially equalproportions of THC and cannabidiol (CBD) as the major cannabinoids.

Sublingual and inhaled CBME preparations have been developed, to achieverapid absorption of the type seen from smoking cannabis, and minimiseabsorption by the oral route, which is subject to first pass metabolism.Evidence collected from pooled phase 2 “n of 1” studies (single casewithin patient crossover studies)^(5,10) has indicated that these routesof administration are not associated with the titration problems of theoral route. CBME dosing is similar to patient controlled analgesia(PCA), most commonly used to deliver opioids for control ofpost-operative pain. Small increments are delivered each time patientsrequire them, up to a maximum daily limit. The phase 2 “n of 1” datahave helped to define the effective dose delivered per actuation, andthe recommended maximum doses. The data also indicate that thetherapeutic benefits of CBMEs are delivered at doses below those whichcause a sensation of a ‘high’, and that onset of the ‘high’ may be anindicator of overtitration.

A large proportion of the MS patients who reported peripheral pain aspart of their symptomatology in the “n of 1” studies showed markedimprovement in pain scores with CBME therapy, usually with fewpersisting side-effects once the optimum dose had been reached.¹⁰Peripheral MS pain may have a neuropathic element but is oftenmultifactorial. Pain of purely neuropathic origin in MS is difficult todiagnose clinically. Studies were set up to investigate and study theefficacy of CBME in relieving neuropathic pain and chronic painfollowing brachial plexus injury. In this condition, chronic pain isattributed to nerve injury, that is, it is neuropathic in origin.

Of primary interest in this study is the efficacy of CBME in relievingneuropathic pain, in comparison to placebo. Brachial plexus injuries mayfollow stretching caused by shoulder dislocation (dystocia), breachextraction or hyper abduction of the neck in abnormal presentationsduring labour. The injuries can be due to simple stretching, haemorrhagewithin a nerve, tearing of the nerve or root or avulsion of the rootswith associated cervical cord injury. The injuries may also be due totrauma of the clavicle or humerus or subluxation of the shoulder orcervical spine. There are a number of other conditions such as ERB'sPalsy (upper brachial plexus injury) (lower plexus injury). All of theseconditions are examples of neuropathic pain and are responsible forconsiderable morbidity. The prognosis for recovery in any of theseconditions is poor and the pain associated with them is excruciating. Todate there is very little than can be done to relieve pain in patientswith these conditions.

Surprisingly, it has been found that extracts of cannabis containing asprincipal cannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol(CBD) in differing proportions are not only effective, but are so at lowdoses. In this regard the applicant has previously determined that inorder to treat pain in Multiple Sclorosis patients it has typically beennecessary to provide a daily dose in the range of 30-50 mg. Thus, theterm low dose as used herein refers to a mean daily dose of less than 40mg.

DESCRIPTION OF THE INVENTION

According to a first aspect of the present invention there is providedthe use of one or more cannabinoids in the manufacture of a medicamentfor use in the treatment of neuropathic or chronic pain.

In one embodiment the medicament is provded in a form capable ofdelivering a mean daily dose of less than 37.5 mg.

Where the medicament is packaged for delivery as e.g. a sub lingual orbuccal spray a typical mean daily dose will be less than 25 mg, andtypically in the range 5-25 mg.

Prefered cannabinoids are THC and/or CBD, more preferably in the form ofa CBME.

According to a second aspect of the present invention there is providedthe use of one or more cannabinoids in the manufacture of a medicamentfor use in the treatment of sleep disturbance.

The invention is further described, by way of example only, withreference to the following Examples and Figs in which:

FIG. 1 shows diary card data for treatments with a high THC or THC/CBDCBME. Pain Score is compared to baseline and placebo;

FIG. 2 shows diary card data showing sleep disturbance scores (changefrom baseline) for treatments with a high THC or THC/CBD CBME;

FIG. 3 shows diary card data showing sleep disturbance scores fortreatments with a high THC or THC/CBD CBME. Sleep disturbance iscompared to baseline and placebo.

FIG. 4 shows pain review scores treatments with a high THC or THC/CBDCBME.

In clinical trials of cannabis extracts, fractional doses of 2.5 mg weregiven to patients with conditions such as the pain of multiple sclerosisto achieve a total daily dose of approximately 40-50 mg of THC or thisdose of THC combined with an equal quantity of CBD. In refractorycondition such as brachial plexus avulsion (BPA) it might be expectedthat higher doses would be required which would take the total dailydose into the range where cognitive impairment was produced in patients.Surprisingly it was found that patients with BPA who were treated withthe same preparations obtained significant relief at doses ofapproximately one half of this level. It was also noted that objectivemeasurements of pain (box scale 11—a validated pain score) showed thatTHC and CBD produced statistically significant reductions in BS11 painscore and both were highly significantly different from placebo and baseline scores. Sleep disturbance was also reduced by THC, and THC incombination with CBD, and there was also an improvement in sleep qualityat week 2. Both THC and CBD produced statistically highly significantimprovement.

EXAMPLE 1

A clinical trial was carried out in 48 patients with chronic pain due tobrachial plexus injury. This was a double blind, randomised, three-waycrossover study comparing two different sublingual cannabis-basedmedicine extracts (CBMEs) with placebo. The active treatments were givenin the form of a sublingual spray. Each spray contained 2.5 mg of THC or2.5 mg of THC plus 2.5 mg of CBD in the form of an alcoholic solution ofa cannabis extract. The patients titrated the dose up to the level atwhich pain relief was obtained; assessments were made by the patientdiary scores and by the clinicians and nursing staff.

FIG. 1 shows the diary card scores based on the box score 11 (BS11) incomparisons with placebo. The mean number of sprays for the patientsreceiving THC was 7.26 and for the 1:1 ratio THC:CBD was 6.93, comparedwith 7.15 for placebo. These doses correspond to total daily doses ofapproximately 18 mg for THC and 17 mg when THC was given in conjunctionwith CBD.

A further surprising finding was that the number of sleep disturbancesin these patients (who have their sleep duration and quality frequentlydisturbed) obtained improvement in this parameter. FIGS. 2 and 3 showthat sleep disturbance scores at week 2 were highly significantlystatistically improved both with THC and the THC:CBD combinationcompared with placebo.

FIG. 4 shows pain review scores showing the effect of THC and THC:CBD in1:1 ratio at week 2. The differences from placebo was highlysignificantly statistically, not only by diary card but by mean painreview score (clinician assessment).

Significantly the relief of pain in these patients from the cannabisextract was achieved at doses which did not cause significant cognitiveimpairment.

COMPARATIVE EXAMPLE

In previous studies, which examined the effect of cannabis-basedmedicine on pain relief in multiple sclerosis, pain relief was typicallyachieved in the range 25-50 mg/day approximately.

It is therefore surprising that in patients with neuropathic pain,particularly brachial plexus pain, which is notoriously difficult totreat, relief was obtained at lower doses.

REFERENCES

-   1. Berman J, Birch R, Anand P. Pain following human brachial plexus    injury with spinal cord root avulsion and the effect of surgery.    Pain 1997; 75:199-207.-   2. Mechoulam R. Cannabinoid chemistry. In: Marijuana—chemistry,    pharmacology, metabolism and clinical effects. Mechoulam R ed.    Academic Press, London. 1973:1-99.-   3. Therapeutic uses of cannabis. British Medical Association. 1997.    1-6. Harwood Academic Publishers. Morgan DR ed.-   4. Ashton CH. Adverse effects of cannabis and cannabinoids. Br J    Anaesth 1999; 83:637-49.-   5. Investigator Brochure—Cannabis based medicine extract sublingual    formulations. GW Pharmaceuticals plc, February 2001, Edition 5.-   6. Grinspoon L, Bakalar J B. Marijuana, the forbidden    medicine. 1993. Yale University Press, 138.-   7. Prescribers Journal 1998; 38.4:213.-   8. Porter J, Jick H. Addiction rare in patients treated with    narcotics. N Engl J Med 1980; 802:123.-   9. Portenoy R K. Chronic opioid therapy in non-malignant pain. J    Pain Symptom Manage 1990; 5 (Suppl 1):46-62.-   10. Unpublished data. GW Pharmaceuticals plc.-   11. House of Lords Select Committee on Science and Technology:    Cannabis: The scientific and medical evidence. 1998; 9^(th) Report.-   12. Petro D J, Ellenberger C. Treatment of human spasticity with Δ⁹    tetrahydrocannabinol. J Clin Pharmacol 1981; 21:413S416S.-   13. Ungerleider J T, Andrysiak T. Fairbanks L et al. Delta-9-THC in    the treatment of spasticity associated with multiple sclerosis. Adv    Alc Subs Abuse 1988; 7:39-50.

1. A method of treating brachial plexus avulsion in a human patientcomprising administering to a patient in need thereof an effectiveamount one or more cannabinoids. 2.-9. (canceled)
 10. The method asclaimed in claim 1 which additionally involves the treatment ofneuropathic pain caused by brachial plexus avulsion.
 11. The method asclaimed in claim 1 which additionally involves the treatment of sleepdisturbance caused by brachial plexus avulsion.
 12. The method asclaimed in claim 1, wherein the one or more cannabinoids comprisedelta-9-tetrahydrocannabinol (THC).
 13. The method as claimed in claim1, wherein the one or more cannabinoids comprise cannabidiol (CBD). 14.The method as claimed in claim 1, wherein the one or more cannabinoidscomprise both THC and CBD.
 15. The method as claimed in claim 14,wherein the THC and CBD are provided in a ratio of between 2:1 and 1:2.16. The method as claimed in claim 15, wherein the THC and CBD areprovided in a ratio of substantially 1:1.
 17. The method as claimed inclaim 12, wherein the medicament is provided in a form capable ofdelivering a mean daily dose of less than 37.5 mg THC.
 18. The method asclaimed in claim 12, wherein the medicament is packaged for delivery asa sublingual or buccal spray to provide a daily dose of less than 25 mgTHC.
 19. The method as claimed in claim 1, wherein the cannabinoids arepresent as a cannabis based medicinal extract (CBME).
 20. (canceled)